Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic PAH (IPAH) and patients with disease-associated PAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent RV failure and death has not been tested. Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with severe PAH and NYHA/WHO class IV symptoms includes use of MR antagonists for their diuretic and natriuretic effects, late in the course, once clinical right heart failure has developed. Currently, no well described data exists from randomized clinical trials examining the safety and efficacy of MR antagonist therapy in early stages of PAH. The concept for the protocol received an NIH Bench-to-Bedside Award in 2011 and a formal protocol was initially approved by the NHLBI IRB in September 2012. Subsequently IRB approval was sought and obtained at collaborating sites and various amendments were brought into alignment at all institutions by summer 2013. Subjects undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory and neurohormonal markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5) high-resolution MRI-based determination of pulmonary vascular and RV structure and function. Safety and tolerability of spironolactone in PAH is assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects. To date of the 14 subjects enrolled in our Natural History protocol (13-CC-0012) four have been enrolled in this study (Spironolactone Randomized Interventional Trial). Two of the four subjects have completed the study. Plans for bolstering recruitment and increasing enrollment included: 1) Our lead investigator has been participating at a local pulmonary clinic weekly in order to facilitate communication with clinic staff and PAH patients during regularly scheduled appointments. 2) We continue to present our study to local pulmonary hypertension support groups and as a result, patient self-referrals have ben a significant source of potential subjects. We plan to continue to maintain a close working relationship with the Pulmonary Hypertension Association and are planning future presentations to regional support groups including a new group currently being organized in Southern Maryland. 3) Research nurses continue to conduct periodic visits to local referral sites in order to facilitate communication with clinic staff and PAH patients. 4) In addition to reaching out to regional academic centers we continue to reach out to regional clinical practices. Local pulmonary and cardiology practices, have expressed interest in referring patients.